The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy.

Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sublethal doses of histones in vivo. Suramin also prevented histone-induced lung endothelial cell cytotoxicity in vitro and lung edema, intra-alveolar hemorrhage, and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.

[Morin Improves Experimental Autoimmune Thyroiditis in Rats via NLRP3/Caspase-1 Pathway].

OBJECTIVE: To investigate the effects of morin-regulated NLRP3/Caspase-1 pathway on experimental autoimmune thyroiditis in rats. METHODS: The rats were randomly assigned to 6 groups: control group, experimental autoimmune thyroiditis group (EAT), low-, medium- and high-dose morin groups (post-modeling gavage of 50, 100 and 200 mg/kg morin hydrate per day for 6 weeks) and tripterygium wilfordii polyglycosides group (LGT group, post-modeling gavage of 6.25 mg/kg tripterygium wilfordii polyglycosidesper day for 6 weeks). Except for the control group, the rat model of experimental autoimmune thyroiditis was established by subcutaneous injection of 0.1 mL incomplete Freund's adjuvant containing porcine thyroglobulin. The levels of serum thyroglobulin (TgAb), thyroid peroxidase antibody (TPOAb), triiodothyronine (T3) and tetraiodothyronine (T4) in serum were detected by radioimmunoassay. The mRNA levels of interleukin-17 ( IL-17), interleukin-4 ( IL-4) and interferon γ ( INF- γ) were detected by reverse transcription-polymerase chain reaction. The levels of serum protein carbonyl content, 8-hydroxydeoxyguanosine (8-OHdG), and malondialdehyde (MDA) activity were checked with test kits. Expressions of NLRP3, apoptosis-related speck-like protein (ASC), and Caspase-1 were detected by Western blot. RESULTS: Compared with the EAT group, serum levels of TPOAb, TgAb, T3, and T4 in low-, medium- and high-dose Morin groups and LGT group were reduced ( P<0.01) and the mRNA levels of IL-17, INF-γ and IL-4 were increased ( P<0.01), the protein hydroxyl content, MDA activity, and 8-OHdG levels were reduced ( P<0.01). The levels of NLRP3, ASC and Caspase-1 were reduced ( P<0.01), the levels of 8-OHdG were significantly reduced ( P<0.01), and the levels of NLRP3, ASC and Caspase-1 were significantly reduced ( P<0.01). There were statistically significant differences between the data from the low-dose and the medium-dose Morin groups and the data of the LGT group ( P<0.05), while data from the high-dose Morin group showed no significant difference compared with the data of the LGT group. Data from low-, medium- and high-dose Morin groups showed no statistically significant differences ( P<0.05). CONCLUSION: The findings suggest that Morin improved experimental autoimmune thyroiditis in rats through regulating NLRP3/Caspase-1 pathway.

Full quantum calculation of the rovibrational states and intensities for a symmetric top-linear molecule dimer: Hamiltonian, basis set, and matrix elements.

The rovibrational energy levels and intensities of the CH3F-H2 dimer have been obtained using our recent global intermolecular potential energy surface [X.-L. Zhang et al., J. Chem. Phys. 148, 124302 (2018)]. The Hamiltonian, basis set, and matrix elements are derived and given for a symmetric top-linear molecule complex. This approach to the generation of energy levels and wavefunctions can readily be utilized for studying the rovibrational spectra of other van der Waals complexes composed of a symmetric top molecule and a linear molecule, and may readily be extended to other complexes of nonlinear molecules and linear molecules. To confirm our method, the rovibrational levels of the H2O-H2 dimer have been computed and shown to be in good agreement with experiment and with previous theoretical results. The rovibrational Schrödinger equation has been solved using a Lanczos algorithm together with an uncoupled product basis set. As expected, dimers containing ortho-H2 are more strongly bound than dimers containing para-H2. Energies and wavefunctions of the discrete rovibrational levels of CH3F-paraH2 complexes obtained from the direct vibrationally averaged 5-dimensional potentials are in good agreement with the results of the reduced 3-dimensional adiabatic-hindered-rotor (AHR) approximation. Accurate calculations of the transition line strengths for the orthoCH3F-paraH2 complex are also carried out, and are consistent with results obtained using the AHR approximation. The microwave spectrum associated with the orthoCH3F-orthoH2 dimer has been predicted for the first time.

Top-down Multiscale Approach To Simulate Peptide Self-Assembly from Monomers.

Modeling peptide assembly from monomers on large time and length scales is often intractable at the atomistic resolution. To address this challenge, we present a new approach which integrates coarse-grained (CG), mixed-resolution, and all-atom (AA) modeling in a single simulation. We simulate the initial encounter stage with the CG model, while the further assembly and reorganization stages are simulated with the mixed-resolution and AA models. We have implemented this top-down approach with new tools to automate model transformations and to monitor oligomer formations. Further, a theory was developed to estimate the optimal simulation length for each stage using a model peptide, melittin. The assembly level, the oligomer distribution, and the secondary structures of melittin simulated by the optimal protocol show good agreement with prior experiments and AA simulations. Finally, our approach and theory have been successfully validated with three amyloid peptides (ß-amyloid 16-22, GNNQQNY fragment from the yeast prion protein SUP35, and α-synuclein fibril 35-55), which highlight the synergy from modeling at multiple resolutions. This work not only serves as proof of concept for multiresolution simulation studies but also presents practical guidelines for further self-assembly simulations at more physically and chemically relevant scales.

Enantioselective Electrophilic Aromatic Nitration: A Chiral Auxiliary Approach.

Enantioselective electrophilic aromatic nitration methodology is needed to advance chirality-assisted synthesis (CAS). Reported here is an enantioselective aromatic nitration strategy operating with chiral diester auxiliaries, and it provides an enantioselective synthesis of a C3v -symmetric tribenzotriquinacene (TBTQ). These axially-chiral structures are much sought-after building blocks for CAS, but they were not accessible prior to this work in enantioenriched form without resolution of enantiomers. This nitration strategy controls the stereochemistry of threefold nitration reactions from above the aromatic rings with chiral diester arms. Dicarbonyl-to-arenium chelation rigidifies the reaction systems, so that remote stereocenters position the ester-directing groups selectively over specific atoms of the TBTQ framework. Closely guided by computational design, a more selective through-space directing arm was first predicted with density functional theory (DFT), and then confirmed in the laboratory, to outperform the initial structural design. This enantio- and regioselective TBTQ synthesis opens a new pathway to access building blocks for CAS.

Nascent energy distribution of the Criegee intermediate CH2OO from direct dynamics calculations of primary ozonide dissociation.

Ozonolysis produces chemically activated carbonyl oxides (Criegee intermediates, CIs) that are either stabilized or decompose directly. This branching has an important impact on atmospheric chemistry. Prior theoretical studies have employed statistical models for energy partitioning to the CI arising from dissociation of the initially formed primary ozonide (POZ). Here, we used direct dynamics simulations to explore this partitioning for decomposition of c-C2H4O3, the POZ in ethylene ozonolysis. A priori estimates for the overall stabilization probability were then obtained by coupling the direct dynamics results with master equation simulations. Trajectories were initiated at the concerted cycloreversion transition state, as well as the second transition state of a stepwise dissociation pathway, both leading to a CI (H2COO) and formaldehyde (H2CO). The resulting CI energy distributions were incorporated in master equation simulations of CI decomposition to obtain channel-specific stabilized CI (sCI) yields. Master equation simulations of POZ formation and decomposition, based on new high-level electronic structure calculations, were used to predict yields for the different POZ decomposition channels. A non-negligible contribution of stepwise POZ dissociation was found, and new mechanistic aspects of this pathway were elucidated. By combining the trajectory-based channel-specific sCI yields with the channel branching fractions, an overall sCI yield of (48 ± 5)% was obtained. Non-statistical energy release was shown to measurably affect sCI formation, with statistical models predicting significantly lower overall sCI yields (∼30%). Within the range of experimental literature values (35%-54%), our trajectory-based calculations favor those clustered at the upper end of the spectrum.

Analytic Morse/long-range potential energy surfaces and "adiabatic-hindered-rotor" treatment for a symmetric top-linear molecule dimer: A case study of CH3F-H2.

A first effective six-dimensional ab initio potential energy surface (PES) for CH3F-H2 which explicitly includes the intramolecular Q3 stretching normal mode of the CH3F monomer is presented. The electronic structure computations have been carried out at the explicitly correlated coupled cluster level of theory [CCSD(T)-F12a] with an augmented correlation-consistent triple zeta basis set. Five-dimensional analytical intermolecular PESs for ν3(CH3F) = 0 and 1 are then obtained by fitting the vibrationally averaged potentials to the Morse/Long-Range (MLR) potential function form. The MLR function form is applied to the nonlinear molecule-linear molecule case for the first time. These fits to 25 015 points have root-mean-square deviations of 0.74 cm-1 and 0.082 cm-1 for interaction energies less than 0.0 cm-1. Using the adiabatic hindered-rotor approximation, three-dimensional PESs for CH3F-paraH2 are generated from the 5D PESs over all possible orientations of the hydrogen monomer. The infrared and microwave spectra for CH3F-paraH2 dimer are predicted for the first time. These analytic PESs can be used for modeling the dynamical behavior in CH3F-(H2)N clusters, including the possible appearance of microscopic superfluidity.

Potential energy surface stationary points and dynamics of the F- + CH3I double inversion mechanism.

Direct dynamics simulations were performed to study the SN2 double inversion mechanism SN2-DI, with retention of configuration, for the F- + CH3I reaction. Previous simulations identified a transition state (TS) structure, i.e. TS0, for the SN2-DI mechanism, including a reaction path. However, intrinsic reaction coordinate (IRC) calculations from TS0 show it is a proton transfer (PT) TS connected to the F-HCH2I SN2 pre-reaction complex and the FHCH2I- proton transfer post-reaction complex. Inclusion of TS0 in the SN2-DI mechanism would thus involve non-IRC atomistic dynamics. Indeed, trajectories initiated at TS0, with random ensembles of energies as assumed by RRKM theory, preferentially form the SN2-DI products and ∼70% follow the proposed SN2-DI pathway from TS0 to the products. In addition, the Sudden Vector Projection (SVP) method was used to identify which CH3I vibrational mode excitations promote access to TS0 and the SN2-DI mechanism. Results of F- + CH3I simulations, with SVP specified mode excitations, are disappointing. With the CH3 deformations of CH3I excited, the SN2 single inversion mechanism is the dominant pathway. If the CH stretch modes are also excited, proton transfer dominates the reaction. SN2-DI occurs, but with a very small probability of ∼1%. The reasons behind these results are discussed.

The origins of intra- and inter-molecular vibrational couplings: A case study of H2O-Ar on full and reduced-dimensional potential energy surface.

The origin and strength of intra- and inter-molecular vibrational coupling is difficult to probe by direct experimental observations. However, explicitly including or not including some specific intramolecular vibrational modes to study intermolecular interaction provides a precise theoretical way to examine the effects of anharmonic coupling between modes. In this work, a full-dimension intra- and inter-molecular ab initio potential energy surface (PES) for H2O-Ar, which explicitly incorporates interdependence on the intramolecular (Q1, Q2, Q3) normal-mode coordinates of the H2O monomer, has been calculated. In addition, four analytic vibrational-quantum-state-specific PESs are obtained by least-squares fitting vibrationally averaged interaction energies for the (v1, v2, v3) = (0, 0, 0), (0, 0, 1), (1, 0, 0), (0, 1, 0) states of H2O to the three-dimensional Morse/long-range potential function. Each vibrationally averaged PES fitted to 442 points has root-mean-square (rms) deviation smaller than 0.15 cm(-1), and required only 58 parameters. With the 3D PESs of H2O-Ar dimer system, we employed the combined radial discrete variable representation/angular finite basis representation method and Lanczos algorithm to calculate rovibrational energy levels. This showed that the resulting vibrationally averaged PESs provide good representations of the experimental infrared data, with rms discrepancies smaller than 0.02 cm(-1) for all three rotational branches of the asymmetric stretch fundamental transitions. The infrared band origin shifts associated with three fundamental bands of H2O in H2O-Ar complex are predicted for the first time and are found to be in good agreement with the (extrapolated) experimental values. Upon introduction of additional intramolecular degrees of freedom into the intermolecular potential energy surface, there is clear spectroscopic evidence of intra- and intermolecular vibrational couplings.

[Clinical characteristics of pediatric hemorrhagic fever with renal syndrome].

OBJECTIVE: To study the clinical characteristics of pediatric hemorrhagic fever with renal syndrome (HFRS), and to improve its understanding so as to reduce the misdiagnosis. METHODS: A retrospective analysis was performed on the clinical data of 26 children with HFRS between January 2009 and December 2012. RESULTS: The age of disease onset was mainly distributed between 7 and 14 years (23 cases, 88%), and the male-to-female ratio was 1.89:l. The clinical manifestations of pediatric HFRS varied. The early symptoms resembled those of a cold, and in the course of HFRS, most patients developed digestive symptoms such as vomiting and abdominal pain. The laboratory examinations usually implicated platelet changes, and the imaging examinations revealed polyserous effusions. The prominent complication was myocardial injury. CONCLUSIONS: Pediatric HFRS mainly occurs in school-age children, more commonly in males. HFRS does not have typical clinical manifestations or symptoms, so it should be distinguished from cold or appendicitis at the early stage. When applying the fluid replacement therapy, the cardiac function should be carefully monitored in case of heart failure.

Analytical Morse/long-range model potential and predicted infrared and microwave spectra for a symmetric top-atom dimer: a case study of CH3F-He.

Four-dimensional ab initio intermolecular potential energy surfaces (PESs) for CH3F-He that explicitly incorporates dependence on the Q3 stretching normal mode of the CH3F molecule and are parametrically dependent on the other averaged intramolecular coordinates have been calculated. Analytical three-dimensional PESs for v3(CH3F) = 0 and 1 are obtained by least-squares fitting the vibrationally averaged potentials to the Morse/Long-Range potential function form. With the 3D PESs, we employ Lanczos algorithm to calculate rovibrational levels of the dimer system. Following some re-assignments, the predicted transition frequencies are in good agreement with experimental microwave data for ortho-CH3F, with the root-mean-square deviation of 0.042 cm(-1). We then provide the first prediction of the infrared and microwave spectra for the para-CH3F-He dimer. The calculated infrared band origin shifts associated with the ν3 fundamental of CH3F are 0.039 and 0.069 cm(-1) for para-CH3F-He and ortho-CH3F-He, respectively.

An intramolecular vibrationally excited intermolecular potential for He-OCS: Globally tested by simulation of vibrational shifts for OCS in HeNN = 1 - 100 Clusters.

An effective four-dimensional ab initio potential energy surface (PES) for He-OCS, which explicitly incorporates dependence on the intramolecular Q(1) (O-C) stretch normal mode of OCS and is parametrically dependent on its Q(3) (C-S) stretch coordinate has been calculated at the coupled-cluster single double triple/aug-cc-pVQZ level including bond functions. Analytic two-dimensional PESs are obtained by least-squares fitting vibrationally averaged interaction energies for v(1)(OCS)= 0, and 1 to the Morse/long-range potential function form. These fits to 305 points both have root-mean-square (rms) deviation of 0.022 cm(-1), and require only 49 parameters. The resulting vibrationally averaged PESs provide good representations of the experimental microwave and infrared data: for 10 microwave transitions, and 51 infrared transitions of the He-OCS dimer, the rms discrepancies are only 93.2 MHz and 0.003 cm(-1), respectively, which are more than four times better than previous theoretical predictions on their original ab initio potentials. The calculated infrared band origin shift associated with the v(1) fundamental of OCS is blueshifted by 0.082 cm(-1) for He-OCS dimer, which is in good agreement with the experimental value of 0.111 cm(-1). The path integral Monte Carlo algorithm and a first order perturbation theory estimate are used to simulate the ν(1) vibrational band origin frequency shifts of OCS in He(n) clusters for N = 1 - 100 . The predicted vibrational frequency shifts with first a blueshift for small N and then followed by a transition to a redshift for larger N are in excellent agreement with experiment across the whole range of N. These results for increasing N demonstrate the high quality of these potentials and globally test the accuracy not only the near global minimum, but also in regions not accessed by N = 1 He-OCS dimer.

Bromido{dicyclo-hexyl[2'-(dimethyl-amino)biphenyl-2-yl]phosphine-κP}[2-(4,6-dimethyl-pyrimidin-2-yl)ferrocenyl-κC,N]palladium(II) dichloro-methane solvate.

In the title compound, [FePdBr(C(5)H(5))(C(11)H(10)N(2))(C(26)H(36)NP)]·CH(2)Cl(2), the Pd atom displays a distorted square-planar coordination environment. The five-membered metallacycle adopts an envelope conformation with the coordinated cyclo-penta-dienyl C atom 0.4222 (4) Šout of plane. The dihedral angle between the pyrimidinyl ring and substituted cyclo-penta-dienyl ring is 21.47 (2)°. In the crystal structure, the dimeric unit is generated through the C-H⋯π contact via a crystallographic inversion centre, while the C-H⋯Cl contacts in the dimeric centre link the dichlormethane mol-ecules with the Pd complex mol-ecules.